Abstract
Genetic aberrations, in consort with epigenetic factors and the tumor microenvironment, drive tumor progression that ultimately results in unlimited cell proliferation, avoidance of immune destruction, and metastatic potential. The characterization of the genomic landscape of melanocytic tumors has significantly improved our understanding of their pathogenesis. Many clinical and histologic subtypes of melanocytic tumors have been found to harbor characteristic genetic aberrations, which often correlate well with their clinical and pathologic phenotypes. In other cases, the detection of genetic aberrations has improved the genotype-based prognostic stratification of melanocytic tumors that are clinically or histologically similar but exhibit differing biological behavior. With the introduction of mechanism-based treatment strategies, genetic markers have also become important predictors of treatment responses, e.g., BRAF mutations determine the therapeutic response to BRAF inhibitors; or high mutational burden in melanoma is associated with favorable response to immunotherapy. However, despite considerable enthusiasm about our improved understanding of genetic aberrations in melanocytic tumors, there have also been sobering results. For example, many genetic tests aiming to better distinguish benign and malignant neoplasms have not fullfilled their expectations, in part, because numerous nongenetic factors, including epigenetic dynamics, cell identity, tumor microenvironment, and the immune system, also influence clinical behavior. Additionally, tumor progression, resulting from a stepwise acquisition of genetic aberrations, implies a continuous spectrum of biologic behavior in melanocytic tumors rather than a clear-cut binary division between “benign” and “malignant.” Furthermore, although numerous recurrent gene alterations in melanocytic tumors have been identified, the functional, diagnostic, and prognostic implications of many of these alterations are yet to be elucidated.
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Griewank, K.G., Murali, R., Wiesner, T. (2019). Molecular Pathology and Genomics of Melanoma. In: Balch, C., et al. Cutaneous Melanoma. Springer, Cham. https://doi.org/10.1007/978-3-319-46029-1_41-1
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